Can Certain Genotypes Predispose to Poor Asthma Control in Children? A Pharmacogenetic Study of 9 Candidate Genes in Children with Difficult Asthma

Objective

We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control.

Methods

A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma.

Key Results

The results indicated that LTA4H A-9188>G, TNFα G-308>A and IL-4Rα A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p = 0.019 and p = 0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4Rα A1199>C, IL-4Rα T1570>C and IL-4Rα A1727>G and CA haplotype of TNFα C-863>A and TNFα G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p = 0.04 and p = 0.018, respectively).

Conclusions and Clinical Relevance

The study revealed multiple SNPs and haplotypes in LTA4H, TNFα and IL4-Rα genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit.     

Effectiveness of Music Education for the Improvement of Reading Skills and Academic Achievement in Young Poor Readers: A Pragmatic Cluster-Randomized,Controlled Clinical Trial

Introduction

Difficulties in word-level reading skills are prevalent in Brazilian schools and may deter children from gaining the knowledge obtained through reading and academic achievement. Music education has emerged as a potential method to improve reading skills because due to a common neurobiological substratum.

Objective

To evaluate the effectiveness of music education for the improvement of reading skills and academic achievement among children (eight to 10 years of age) with reading difficulties.

Method

235 children with reading difficulties in 10 schools participated in a five-month, randomized clinical trial in cluster (RCT) in an impoverished zone within the city of São Paulo to test the effects of music education intervention while assessing reading skills and academic achievement during the school year. Five schools were chosen randomly to incorporate music classes (n = 114), and five served as controls (n = 121). Two different methods of analysis were used to evaluate the effectiveness of the intervention: The standard method was intention-to-treat (ITT), and the other was the Complier Average Causal Effect (CACE) estimation method, which took compliance status into account.

Results

The ITT analyses were not very promising; only one marginal effect existed for the rate of correct real words read per minute. Indeed, considering ITT, improvements were observed in the secondary outcomes (slope of Portuguese = 0.21 [p<0.001] and slope of math = 0.25 [p<0.001]). As for CACE estimation (i.e., complier children versus non-complier children), more promising effects were observed in terms of the rate of correct words read per minute [β = 13.98, p<0.001] and phonological awareness [β = 19.72, p<0.001] as well as secondary outcomes (academic achievement in Portuguese [β = 0.77, p<0.0001] and math [β = 0.49, p<0.001] throughout the school year).

Conclusion

The results may be seen as promising, but they are not, in themselves, enough to make music lessons as public policy.     

Risky Food Safety Behaviors Are Associated with Higher Bmi and Lower Healthy Eating Self-Efficacy and Intentions among African American Churchgoers in Baltimore

Background

There are an estimated 9.4 million cases of foodborne illness each year. Consumers have a key role in preventing foodborne illness, but differences in the practice of food safety behaviors exist, increasing risk for certain groups in the population. Identifying groups who are more likely to practice risky food safety behaviors can assist in development of interventions to reduce the disease burden of foodborne illnesses. The purpose of this investigation was to examine the relationships of health indicators and psychosocial factors with self-reported food safety behaviors.

Methods and Findings

Data were collected via questionnaire from 153 African Americans who attend churches in Baltimore City. Individuals reported high overall concern with food safety (mean score: 0.80±0.49 on a scale of −1 to +1) and practiced food safety behaviors with moderate overall frequency (mean score: 5.26±4.01 on a scale of −12 to +12), with considerable variation in reported frequencies depending on the food safety behavior. After adjusting for demographic variables, food safety behaviors were significantly associated with BMI and psychosocial variables. Riskier food safety behaviors were associated with higher body mass index (BMI) (β = −0.141 95%CI (−0.237, −0.044), p = 0.004). Self-efficacy for healthy eating (standard β [std. β] = 0.250, p = 0.005) and healthy eating intentions (std. β = 0.178, p = 0.041) were associated with better food safety behaviors scores.

Conclusions

These results show important relationships between weight-related health indicators, psychosocial factors and food safety behaviors that have not previously been studied. Interventions tailored to higher-risk populations have the potential to reduce the burden of food-related illnesses. Additional studies are needed to further investigate these relationships with larger and more diverse samples.     

Tumor Necrosis Factor Alpha Blocking Agents as Treatment for Ulcerative Colitis Intolerant or Refractory to Conventional Medical Therapy: A Meta-Analysis

Background

Efficacy of tumor necrosis factor alpha (TNF-α) blockers for treatment of ulcerative colitis that is unresponsive to conventional therapy is unclear due to recent studies yielding conflicting results.

Aim

To assess the efficacy and safety of anti-TNF-α agents for treatment of ulcerative colitis patients who were intolerant or refractory to conventional medical therapy.

Methods

Pubmed, Embase, and the Cochrane database were searched. Analysis was performed on randomized controlled trials that assessed anti-TNF-α therapy on ulcerative colitis patients that had previously failed therapy with corticosteroids and/or immunosuppressants. The primary outcome focused on was the frequency of patients that achieved clinical remission. Further trial outcomes of interest included rates of remission without patient use of corticosteroids during the trial, extent of mucosal healing, and the number of cases that resulted in colectomy and serious side effects.

Results

Eight trials from seven studies (n = 2122) met the inclusion criteria and were thus included during analysis. TNF-α blockers demonstrated clinical benefit as compared to placebo control as evidenced by an increased frequency of clinical remission (p<0.00001), steroid-free remission (p = 0.01), endoscopic remission (p<0.00001) and a decrease in frequency of colectomy (p = 0.03). No difference was found concerning serious side effects (p = 0.05). Three small trials (n = 57) comparing infliximab to corticosteroid treatment, showed no difference in frequency of clinical remission (p = 0.93), mucosal healing (p = 0.80), and requirement for a colectomy (p = 0.49). One trial compared infliximab to cyclosporine (n = 115), wherein no difference was found in terms of mucosal healing (p = 0.85), colectomy frequency (p = 0.60) and serious side effects (p = 0.23).

Conclusion

TNF-α blockers are effective and safe therapies for the induction and maintenance of long-term remission and prevention of treatment by colectomy for patients with refractory ulcerative colitis where conventional treatment was previously ineffective. Furthermore, infliximab and cyclosporine were found to be comparable for treating acute severe steroid-refractory ulcerative colitis.     

No Association between Low Birth Weight and Cardiovascular Risk Factors in Early Adulthood: Evidence from S?o Paulo,Brazil

Background

A growing literature suggests that low birth weight increases the risk of poor health outcomes in adulthood. We tested this hypothesis among young adults living in São Paulo State, Brazil.

Methods and Findings

To identify the effects of low birth weight on young adulthood outcomes, a medical assessment of 297 individuals born between 1977 and 1989 was conducted at a primary care unit in São Paulo State, Brazil. We analyzed body mass index (BMI), waist-hip ratio, blood pressure, fasting glucose and total cholesterol levels using linear and logistic regressions. Low birth was negatively associated with BMI (β = −2.0, 95% CI: −3.69, −0.27, p = 0.02), fasting glucose levels (β = −1.9, 95% CI: −3.9, −0.07, p = 0.05), waist-hip ratio (β = −0.03, 95% CI: −0.07, −0.01, p = 0.10), systolic blood pressure (β = −3.32, 95% CI: −7.60, 0.96, p = 0.12), and total cholesterol levels (β = −3.19, 95% CI: −16.43, 10.05, p = 0.636). Low birth weight was also associated with lower odds of young adults being overweight and obese, but neither association was statistically significant. Weight gain in the first 12 months of life was associated with higher adult BMI (β = 0.79, 95% CI: −0.0455, 1.623, p = 0.064) and blood pressure (β = 2.79, 95% CI: 0.22, 5.35, p = 0.034). No associations were found between low birth weight and early life (catch-up) growth.

Conclusions

Low birth weight was not associated with poor health outcomes among young adults in Brazil. These results appear inconsistent with the original Barker hypothesis, but will need to be corroborated in larger samples with longer follow-ups to allow a more general evaluation of the validity of the hypothesis in low and middle income countries.     

The Association between a Vegetarian Diet and Cardiovascular Disease (CVD) Risk Factors in India: The Indian Migration Study

Background

Studies in the West have shown lower cardiovascular disease (CVD) risk among people taking a vegetarian diet, but these findings may be confounded and only a minority selects these diets. We evaluated the association between vegetarian diets (chosen by 35%) and CVD risk factors across four regions of India.

Methods

Study participants included urban migrants, their rural siblings and urban residents, of the Indian Migration Study from Lucknow, Nagpur, Hyderabad and Bangalore (n = 6555, mean age-40.9 yrs). Information on diet (validated interviewer-administered semi-quantitative food frequency questionnaire), tobacco, alcohol, physical history, medical history, as well as blood pressure, fasting blood and anthropometric measurements were collected. Vegetarians ate no eggs, fish, poultry or meat. Using robust standard error multivariate linear regression models, we investigated the association of vegetarian diets with blood cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides, fasting blood glucose (FBG), systolic (SBP) and diastolic blood pressure (DBP).

Results

Vegetarians (32.8% of the study population) did not differ from non-vegetarians with respect to age, use of smokeless tobacco, body mass index, and prevalence of diabetes or hypertension. Vegetarians had a higher standard of living and were less likely to smoke, drink alcohol (p<0.0001) and were less physically active (p = 0.04). In multivariate analysis, vegetarians had lower levels of total cholesterol (β = −0.1 mmol/L (95% CI: −0.03 to −0.2), p = 0.006), triglycerides (β = −0.05 mmol/L (95% CI: −0.007 to −0.01), p = 0.02), LDL (β = −0.06 mmol/L (95% CI: −0.005 to −0.1), p = 0.03) and lower DBP (β = −0.7 mmHg (95% CI: −1.2 to −0.07), p = 0.02). Vegetarians also had decreases in SBP (β = −0.9 mmHg (95% CI: −1.9 to 0.08), p = 0.07) and FBG level (β = −0.07 mmol/L (95% CI: −0.2 to 0.01), p = 0.09) when compared to non-vegetarians.

Conclusion

We found beneficial association of vegetarian diet with cardiovascular risk factors compared to non-vegetarian diet.     

Insulin Sensitivity from Preschool to School Age in Patients with Severe Obesity

Background

Insulin sensitivity decreases at puberty transition, but little information has been provided on its earlier time-course. Aim of the present study was to describe the time-course of insulin sensitivity in severely obese children at the transition from preschool to school age.

Research design and methods

Retrospective study of a cohort of 47 severely obese [Body Mass Index (BMI) ≥99° percentile] preschoolers evaluated twice, once between 2 and 6 years of age, and once before age 8. Glucose tolerance, Whole Body Insulin Sensitivity Index (WBISI), Insulinogenic Index (IGI); β-cell demand index (BCDI) and Insulin Secretion-Sensitivity Index 2 (ISSI-2) were longitudinally estimated during the oral glucose tolerance test.

Results

After a median follow-up of 2.23 (1–4.52) y, obese patients showed significant decrease in WBISI (p<0.0001), and increase in fasting (p = 0.005) and 2 h glucose (2HG, p = 0.001). One child in preschool age and 4 school age children presented with 2HG between 7.8–11.1 mmol/l. Best predictors of WBISI, 2HG and BCDI in the school age were changes in BMI z-score (R² = 0.309; p = 0.002; β = −0.556), ISSI-2 (R² = 0.465; p<0.0001; β = −0.682), and BMI z-score (R² = 0.246; p = 0.008; 0.496), respectively.

Conclusions

In morbidly obese children, insulin sensitivity seems to decline even before pubertal transition, but changes in total adiposity can only partially explain this variation.     

Low Muscle Strength Is Associated with Metabolic Risk Factors in Colombian Children: The ACFIES Study

Purpose

In youth, poor cardiorespiratory and muscular strength are associated with elevated metabolic risk factors. However, studies examining associations between strength and risk factors have been done exclusively in high income countries, and largely in Caucasian cohorts. The aim of this study was to assess these interactions in schoolchildren in Colombia, a middle income Latin American country.

Methods

We measured body mass index, body composition, handgrip strength (HG), cardiorespiratory fitness (CRF) and metabolic risk factors in 669 low-middle socioeconomic status Colombian schoolchildren (mean age 11.52±1.13, 47% female). Associations between HG, CRF and metabolic risk factors were evaluated.

Results

HG and CRF were inversely associated with blood pressure, HOMA index and a composite metabolic risk score (p<0.001 for all) and HG was also inversely associated with triglycerides and C-reactive protein (CRP) (both p<0.05). Associations between HG and risk factors were marginally weakened after adjusting for CRF, while associations between CRF and these factors were substantially weakened after adjusting for HG. Linear regression analyses showed inverse associations between HG and systolic BP (β = −0.101; p = 0.047), diastolic BP (β = −0.241; p> = 0.001), HOMA (β = −0.164; p = 0.005), triglycerides (β = −0.583; p = 0.026) and CRP (β = −0.183; p = 0.037) but not glucose (p = 0.698) or HDL cholesterol (p = 0.132). The odds ratios for having clustered risk in the weakest quartile compared with the strongest quartile were 3.0 (95% confidence interval: 1.81–4.95).

Conclusions

In Colombian schoolchildren both poorer handgrip strength/kg body mass and cardiorespiratory fitness were associated with a worse metabolic risk profile. Associations were stronger and more consistent between handgrip and risk factors than between cardiorespiratory fitness and these risk factors. Our findings indicate the addition of handgrip dynamometry to non-invasive youth health surveillance programs would improve the accuracy of the assessment of cardio-metabolic health.     

Potential Role of M. tuberculosis Specific IFN-γ and IL-2 ELISPOT Assays in Discriminating Children with Active or Latent Tuberculosis

Background

Although currently available IGRA have been reported to be promising markers for TB infection, they cannot distinguish active tuberculosis (TB) from latent infection (LTBI).

Objective

Children with LTBI, active TB disease or uninfected were prospectively evaluated by an in-house ELISPOT assay in order to investigate possible immunological markers for a differential diagnosis between LTBI and active TB.

Methods

Children at risk for TB infection prospectively enrolled in our infectious disease unit were evaluated by in-house IFN-γ and IL-2 based ELISPOT assays using a panel of Mycobacterium tuberculosis antigens.

Results

Twenty-nine children were classified as uninfected, 21 as LTBI and 25 as active TB cases (including 5 definite and 20 probable cases). Significantly higher IFN-γ ELISPOT responses were observed in infected vs. uninfected children for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p = 0.003), and AlaDH (p = 0.001), while differences were not significant considering Ag85B (p = 0.063), PstS1 (p = 0.512), and HspX (16 kDa) (p = 0.139). IL-2 ELISPOT assay responses were different for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p<0.0001), HspX (16 kDa) (p<0.0001), PstS1 (p<0.0001) and AlaDH (p = 0.001); but not for Ag85B (p = 0.063). Comparing results between children with LTBI and those with TB disease differences were significant for IFN-γ ELISPOT only for AlaDH antigen (p = 0.021) and for IL-2 ELISPOT assay for AlaDH (p<0.0001) and TB 10.3 antigen (p = 0.043). ROC analyses demonstrated sensitivity of 100% and specificity of 81% of AlaDH-IL-2 ELISPOT assay in discriminating between latent and active TB using a cut off of 12.5 SCF per million PBMCs.

Conclusion

Our data suggest that IL-2 based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB.     

Adiposity Predicts Cognitive Decline in Older Persons with Diabetes: A 2-Year Follow-Up

Background

The mechanisms related to cognitive impairment in older persons with Type 2 diabetes (DM) remains unclear. We tested if adiposity parameters and body fat distribution could predict cognitive decline in older persons with DM vs. normal glucose tolerance (NGT).

Methodology

693 older persons with no dementia were enrolled: 253 with DM in good metabolic control; 440 with NGT (age range:65–85 years). Longitudinal study comparing DM and NGT individuals according to the association of baseline adiposity parameters (body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC) and total body fat mass) to cognitive change (Mini Mental State Examination (MMSE), a composite score of executive and attention functioning (CCS) over time.

Findings

At baseline, in DM participants, MMSE correlated with WHR (β = −0.240; p = 0.043), WC (β = −0.264; p = 0.041) while CCS correlated with WHR (β = −0.238; p = 0.041), WC (β = −0.326; p = 0.013) after adjusting for confounders. In NGT subjects, no significant correlations were found among any adiposity parameters and MMSE, while CCS was associated with WHR (β = −0.194; p = 0.036) and WC (β = −0.210; p = 0.024). Participants with DM in the 3^rd tertile of total fat mass showed the greatest decline in cognitive performance compared to those in 1^st tertile (tests for trend: MMSE(p = 0.007), CCS(p = 0.003)). Logistic regression models showed that 3^rd vs. 1^st tertile of total fat mass, WHR, and WC predicted an almost two-fold decline in cognitive function in DM subjects at 2^nd yr (OR 1.68, 95%IC 1.08–3.52).

Conclusions

Total fat mass and central adiposity predict an increased risk for cognitive decline in older person with DM.     

Extracellular Matrix Biomarker,Fibulin-1, Is Closely Related to NT-proBNP and Soluble Urokinase Plasminogen Activator Receptor in Patients with Aortic Valve Stenosis (The SEAS Study)

Background

Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS).

Methods

In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo.

Results

During treatment, fibulin-1 became more closely associated with NT-proBNP (β_year0 = 0.10, p = 0.08, β_year1 = 0.16, p = 0.005, β_year4 = 0.22, p<0.001) and suPAR (β_year0 = 0.05, p = 0.34, β_year1 = 0.16, p = 0.006, β_year4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (β_year0 = −0.14, p = 0.005, β_year1 = −0.08, p = 0.11, β_year4 = −0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.R_year0 ² = 0.19, Adj.R_year1 ² = 0.22, Adj.R_year4 ² = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm²/m² (median value), fibulin-1 was more closely associated to NT-proBNP (β_year0 = 0.25, β_year1 = 0.21, β_year4 = 0.22, all p<0.01), and suPAR (β_year0 = 0.09, p = 0.26, β_year1 = 0.23, β_year4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation.

Conclusions

Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load.     

Decreased NK Cell FcRγ in HIV-1 Infected Individuals Receiving Combination Antiretroviral Therapy: a Cross Sectional Study

Background

FcRγ is an immunoreceptor tyrosine-based activation motif (ITAM)-signalling protein essential for immunoreceptor signaling and monocyte, macrophage and NK cell function. Previous study from our laboratory showed that FcRγ is down-regulated in HIV-infected macrophages in vitro. FcRγ expression in immune cells present in HIV-infected individuals is unknown.

Methodology/Principal Findings

We compared FcRγ expression in peripheral blood mononuclear cells isolated from HIV-1-infected individuals receiving combination antiretroviral therapy and healthy, HIV-1-uninfected individuals. FcRγ mRNA and protein levels were measured using quantitative real-time PCR and immunoblotting, respectively. CD56⁺ CD94⁺ lymphocytes isolated from blood of HIV-1 infected individuals had reduced FcRγ protein expression compared to HIV-uninfected individuals (decrease = 76.8%, n = 18 and n = 12 respectively, p = 0.0036). In a second group of patients, highly purified NK cells had reduced FcRγ protein expression compared to uninfected controls (decrease = 50.2%, n = 9 and n = 8 respectively, p = 0.021). Decreased FcRγ expression in CD56+CD94+ lymphocytes was associated with reduced mRNA (51.7%, p = 0.021) but this was not observed for the smaller group of patients analysed for NK cell expression (p = 0.36).

Conclusion/Significance

These data suggest biochemical defects in ITAM-dependent signalling within NK cells in HIV-infected individuals which is present in the context of treatment with combination antiretroviral therapy.     

Association between Apolipoprotein E Gene Polymorphism and the Risk of Coronary Artery Disease in Chinese Population: Evidence from a Meta-Analysis of 40 Studies

Background

Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and coronary artery disease (CAD) risk which developed inconsistent conclusions. To derive a more precise estimation of the relationship in Chinese population, we performed this meta-analysis.

Methods

Databases, including PubMed, EMbase, Web of Science, CBMdisc and CNKI, were searched to get the genetic association studies. Additionally, hand searching of the references of identified articles were performed. All the statistical tests were performed using Review Manager 5.1.2 and Stata 11.0.

Results

We identified a total of 40 studies, including 4,564 CAD cases and 3,985 controls. The results showed evidence for significant association between ApoE ε4 allele and CAD risk (for ε2/ε4 vs. ε3/ε3: OR = 1.86, 95% CI = 1.42–2.43, p<0.00001; for ε3/ε4 vs. ε3/ε3: OR = 2.34, 95% CI = 2.07–2.65, p<0.00001; for ε4/ε4 vs. ε3/ε3: OR = 2.89, 95% CI = 1.87–4.47, p<0.00001; for ε4 allele vs. ε3 allele: OR = 2.11, 95% CI = 1.91–2.35, p<0.00001).

Conclusions

The present meta-analysis suggests an association between ApoE ε4 allele and increased risk of CAD in Chinese population. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.     

Dietary Adequacy of Vitamin D and Calcium among Inuit and Inuvialuit Women of Child-Bearing Age in Arctic Canada: A Growing Concern

Background

Arctic populations are at an increased risk of vitamin D inadequacy due to geographic latitude and a nutrition transition. This study aimed to assess the adequacy of dietary vitamin D and calcium among women of child-bearing age in Arctic Canada.

Methods

This study collected data from 203 randomly selected women of child-bearing age (19-44 years) in Nunavut and the Northwest Territories of Arctic Canada. Cross-sectional surveys using a validated quantitative food frequency questionnaire were analysed to determine the dietary adequacy of vitamin D and calcium and summarize the top foods contributing to vitamin D and calcium intake among traditional food eaters (TFE) and non-traditional food eaters (NTFE).

Results

The response rate was between 69-93% depending on the community sampled. Mean BMIs for both TFE and NTFE were above the normal range. Traditional food eaters had a significantly higher median vitamin D intake compared with non-traditional eaters (TFE = 5.13±5.34 µg/day; NTFE = 3.5±3.22 µg/day, p = 0·004). The majority of women (87%) were below the Estimated Average Requirements (EAR) for vitamin D. Despite adequate median daily calcium intake in both TFE (1299±798 mg/day) and NTFE (992±704 mg/day; p = 0.0005), 27% of the study population fell below the EAR for calcium. Dairy products contributed the most to intake of vitamin D (TFE = 30.7%; NTFE = 39.1%) and calcium (TFE = 25.5%; NTFE = 34.5%).

Conclusions

Inadequate dietary vitamin D intake is evident among Inuit and Inuvialuit women of child-bearing age in Arctic Canada. Promotion of nutrient-rich sources of traditional foods, supplementation protocols and/or expanded food fortification should be considered to address this nutrition concern.     

Biomarker Changes Associated with Tuberculin Skin Test (TST) Conversion: A Two-Year Longitudinal Follow-Up Study in Exposed Household Contacts

Background

A high prevalence (50–80%) of Tuberculin Skin Test Positivity (TST+ ≥10 mm indurations) has been reported in TB endemic countries. This pool forms a huge reservoir for new incident TB cases. However, immune biomarkers associated with TST conversion are largely unknown. The objective of this study was to identify immune biomarkers associated with TST conversion after acute Mycobacterium tuberculosis (MTB) exposure.

Methodology/Principal Findings

A 24 month longitudinal study was carried out in a recently MTB exposed cohort of household contacts (HC = 93; 75% TST+). Control group consisted of unexposed community controls (EC = 59; 46%TST+). Cytokine secretion was assessed in whole blood cultures in response to either mycobacterial culture filtrate (CF) antigens or mitogens (PHA or LPS) using Elisa methodology. Compared to the EC group, the HC group at recruitment (Kruskal-Wallis Test) showed significantly suppressed IFN γ (p = 0.0001), raised IL-10 (p = 0.0005) and raised TNF α (p = 0.001) in response to CF irrespective of their TST status. Seventeen TST-HC, showed TST conversion when retested at 6 months. Post TST conversion (paired t tests) significant increases were observed for CF induced IFN γ (p = 0.038), IL-10 (p = 0.001) and IL-6 (p = 0.006). Cytokine responses were also compared in the exposed HC group with either recent infection [(TST converters (N = 17)] or previous infection [TST+ HC (N = 54)] at 0, 6, 12 and 24 months using ANOVA on repeated measures. Significant differences between the exposed HC groups were noted only at 6 months. CF induced IFN γ was higher in previously infected HC group (p = 0.038) while IL-10 was higher in recently infected HC group (p = 0.041). Mitogen induced cytokine secretion showed similar differences for different group.

Conclusions/Significance

Our results suggest that TST conversion is associated with early increases in IFN γ and IL-10 responses and precedes latency by several months post exposure.     

Plasma Uric Acid Levels Correlate with Inflammation and Disease Severity in Malian Children with Plasmodium falciparum Malaria

Background

Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of ‘parasite-derived’ UA stimulate immune cells to produce inflammatory cytokines in vitro.

Methods and Findings

We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09–1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97–1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNFα (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34–1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl).

Conclusions

Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved. Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00669084","term_id":"NCT00669084"}}NCT00669084     

Contribution of Psychosocial Factors to the Association between Socioeconomic Position and Takeaway Food Consumption

Objective

To examine whether psychosocial factors mediate (explain) the association between socioeconomic position and takeaway food consumption.

Design

A cross-sectional postal survey conducted in 2009.

Setting

Participants reported their usual consumption of 22 takeaway food items, and these were grouped into a “healthy” and “less healthy” index based on each items'' nutritional properties. Principal Components Analysis was used to derive three psychosocial scales that measured beliefs about the relationship between diet and health (α = 0.73), and perceptions about the value (α = 0.79) and pleasure (α = 0.61) of takeaway food. A nutrition knowledge index was also used. Socioeconomic position was measured by highest attained education level.

Subjects

Randomly selected adults (n = 1,500) aged between 25–64 years in Brisbane, Australia (response rate  =  63.7%, N = 903).

Results

Compared with those with a bachelor degree or higher, participants with a diploma level of education were more likely to consume “healthy” takeaway food (p = 0.023) whereas the least educated (high school only) were more likely to consume “less healthy” choices (p = 0.002). The least educated were less likely to believe in a relationship between diet and health (p<0.001), and more likely to have lower nutritional knowledge compared with their highly educated counterparts (p<0.001). Education differences in beliefs about the relationship between diet and health partly and significantly mediated the association between education and “healthy” takeaway food consumption. Diet- and health-related beliefs and nutritional knowledge partly and significantly mediated the education differences in “less healthy” takeaway food consumption.

Conclusions

Interventions that target beliefs about the relationship between diet and health, and nutritional knowledge may reduce socioeconomic differences in takeaway food consumption, particularly for “less healthy” options.     

Serum γ-glutamyl Transferase Levels,Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

Background and Aims

Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis.

Methods

843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT.

Results

By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB).

Conclusions

In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.     

Changes in Natural Killer Cell Activation and Function during Primary HIV-1 Infection

Background

Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.

Methodology/Principal Findings

Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α₄β₇). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32''p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR_pos) NK cells increased following HIV acquisition (p = 0.006), and KIR_pos NK cells were less activated than KIR_neg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).

Conclusions/Significance

Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.